The central theme of the University of Chicago Autoimmune Center of Excellence (UCACE) is tolerance and adaptive immunity in autoimmune diseases. The UCACE has two over-riding goals. The first is to determine how adaptive autoimmunity evolves and is propagated in situ in autoimmune diseases with specific end organ involvement. We will focus on lupus nephritis (LuN) which is the most common severe manifestation of systemic lupus erythematosus (SLE). Progression to renal failure correlates with tubulointerstitial inflammation (TII) and that the immunological processes associated with TII are intrinsic to the kidney. These processes are not fully reflected in the peripheral blood an murine models of SLE do not mimic the in situ adaptive immune responses of human lupus TII. Therefore, animal models cannot substitute for primary studies in humans. During the last cycle of the ACE, we developed novel methods to study in situ immunity in human tissue. We can now clone in situ expressed antibodies, express these antibodies and characterize the antigens they bind. However, identifying the antigens recognized in situ is not sufficient to understand how those B cells are being selected in situ. As described in the Collaborative and Pilot Projects, we have developed novel computational tools to identify both cognate cell:cell interactions and global patterns of cellular organization in human inflammation. In the Collaborative Project, we will extend these studies to other disease states to establish specific and global mechanisms by which in situ tolerance fails in autoimmunity. The second goal to be pursued by the UCACE is complementary to the first. While the first addresses how autoimmunity is propagated in situ, the second examines the consequences of a loss of tolerance, and autoimmunity, in the development of protective immunity to infection. Surprisingly, SLE patients mount more effective humoral immune responses to influenza vaccination than normal controls. In the Primary Project, we will determine if enhanced protective immunity is a consequence of the broader immunoglobulin repertoire associated with SLE and/or if the cytokine milieu of SLE enables better protective immunity. RELEVANCE: The focus of the University of Chicago Autoimmunity is on lupus. Lupus is a severe body-wide autoimmune disease with severe consequences and for which we have few effective therapies. Furthermore, many of these treatments are very toxic. One goal of the UCACE is to better understand lupus which will enable the development of more effective and less toxic therapies. Principal Project: Exploring the mechanistic basis for altered peripheral B cell selection in SLE Project Leader (PL): Wilson, Patrick C. DESCRIPTION (as provided by applicant): In surprising findings from the previous funding period of the UChicago ACE we found that systemic lupus erythematous (SLE) patients generated higher-affinity and more potently neutralizing anti-influenza antibodies (manuscript in preparation). We have also demonstrated this tendency in the Mrl-lpr/lpr mouse model of SLE. These findings suggest one of two primary hypotheses that we believe are of central importance to understanding the cause of SLE. First, there is the possibility that people who make higher affinity antibodies in general are also at a higher risk for lupus. All people likely make autoantibody responses from time to time. However, individuals that are prone to make high affinity antibodies during any immune response may make higher affinity and therefore pathological autoantibodies on occasion that with epitope spreading will result in SLE. The second possibility is that autoimmunity may improve antibody responses. Thus higher-affinity and concomitantly autoimmunity are selected together, increasing the risk for SLE. That is the autoimmune repertoire, or other features associated with autoimmunity such as inflammation, enables more effective antibody responses. In this renewal application, we propose to test various hypotheses to reveal the mechanisms by which SLE patients mount more effective humoral immune responses to influenza and other vaccines. We also noted that unlike control subject antibodies that were somewhat autoreactive, those from SLE patients were uniquely reactive to self-antigens without being polyreactive. These findings suggest that in SLE patients, selection against polyreactivity during peripheral immune responses is intact, supporting a model for lupus pathology in which high-affinity autoantibodies are generated in self-antigen specific responses. In Specific Aim 1 we will perform experiments to explore this hypothesis. In Specific Aims 2 and 3 we will explore the mechanistic basis for generating high affinity, and conversely, autoimmune-prone responses in SLE patients and controls (Aim 2) or in mouse models of autoimmunity (Aim 3). These experiments will provide insight into why autoimmunity might be maintained in the general population. RELEVANCE: We have found that lupus patients make higher affinity antibodies to influenza upon vaccination. This finding suggests that SLE may have resulted from a selective advantage allowing higher affinity antibody responses to pathogens. Understanding the mechanism by which higher affinity and self-reactive antibodies are produced by patients is important for understanding the underlying causes of SLE.